An unexpected michael-aldol-Smiles rearrangement sequence for the synthesis of versatile optically active bicyclic structures by using asymmetric organocatalysis

Article abstract of DOI:10.1002/chem.200903274

A facile and simple organocatalytic procedure to generate optically active 6-alkyl- and 6-aryl-substituted bicyclo[2.2.2]oct-5-en-2-ones is presented. The reaction is catalysed by a 9-amino-9-deoxyepiquinine trifluoroacetic acid salt, which activates α,β-unsaturated cyclic ketones for the 1,4-addition of β-keto benzothiazoyl sulfones in a stereoselective fashion. Subsequent intramolecular aldol reaction and Smiles rearrangement gives rise to important optically active bicycles, which are a common motif in natural products, ligands in asymmetric catalysis and substrates for Cope rearrangements, photochemical reactions, radical cyclisations and metathesis. Different bicyclic structures were obtained by utilisation of various cyclic enones or by performing ring-expanding reactions. Further-more, two possible mechanistic pathways are outlined and discussed.

Full text of DOI:10.1002/chem.200903274

FULL PAPER
DOI: 10.1002/chem.200903274
An Unexpected Michael–Aldol–Smiles Rearrangement Sequence for the
Synthesis of Versatile Optically Active Bicyclic Structures by Using
Asymmetric Organocatalysis
Nicole Holub, Hao Jiang, Marcio W. Paix¼o, Caterina Tiberi, and Karl A. Jørgensen*[a]
Abstract: A facile and simple organo-
catalytic procedure to generate optical-
ly active 6-alkyl- and 6-aryl-substituted
tramolecular aldol reaction and Smiles
rearrangement gives rise to important
optically active bicycles, which are a
common motif in natural products, li-
gands in asymmetric catalysis and sub-
strates for Cope rearrangements, pho-
tochemical reactions, radical cyclisa-
tions and metathesis. Different bicyclic
structures were obtained by utilisation
of various cyclic enones or by perform-
ing ring-expanding reactions. Further-
more, two possible mechanistic path-
ways are outlined and discussed.
bicycloACHTUNGTRENNUNG[2.2.2]oct-5-en-2-ones is present-
ed. The reaction is catalysed by a 9-
amino-9-deoxyepiquinine trifluoroace-
tic acid salt, which activates a,b-unsatu-
rated cyclic ketones for the 1,4-addition
of b-keto benzothiazoyl sulfones in a
stereoselective fashion. Subsequent in-
Keywords: asymmetric catalysis
·
bicycles · enones · organocatalysis ·
Smiles rearrangement
Introduction
pupukeanane class of natural products.[2] On the other hand,
these bicyclic structures have also found application as key
The application of substituted bicyclo
G
intermediates in the synthesis of chiral bicycloACTHNGUTERN[UNG 2.2.2]dienes,
in organic synthesis has been plentiful (Figure 1). Besides
their use as substrates in various photochemical reactions,[1]
for example, in di-p-methane or oxa-di-p-methane rear-
rangements and photoinduced electron-transfer reactions,
they are suitable precursors for the examination of radical
cyclisation reactions, leading to the formation of the unique
tricyclo[4.3.1.03,7]decane framework, which is present in the
serving as effective ligands for asymmetric rhodium-cata-
lysed 1,4-additions as described by the groups of Carreira
and Hayashi.[3] Besides the presence of the bicyclo
ACTHNUGRTENUNG[2.2.2]oct-
5-en-2-one motif in natural products, such as obtunone and
chamaecypanone,[4] it has also been shown that the elabora-
tion of the bicyclic core in anionic oxy-Cope rearrangements
gives rise to functionalised decalin systems, which are con-
tained in a variety of terpenoids and steroids.[5]
Thus far, synthetic approaches to this important class of
compounds have been almost exclusively limited to Diels–
Alder reactions between an electron-deficient alkene and
masked o-benzoquinones, or other 2,4-cyclohexadienone
substitutes.[6] High reaction temperatures and limited substi-
tution patterns are some of the drawbacks of this synthetic
approach. Murakami and Ashida reported the synthesis of
Figure 1. Important applications of substituted bicycloACTHUNRTGNEUNG[2.2.2]oct-5-en-2-
ones.
benzobicycloACTHNUGTRNEUNG[2.2.2]octenones by a nickel-catalysed alkene
insertion,[7] whereas the strategy of Srikrishna et al. relied
on an intramolecular alkylation, starting from carvone and
therefore giving access to chiral bicyclic structures.[8] More
recently, a racemic approach involving intermolecular Mi-
chael addition followed by intramolecular aldol condensa-
tion has been described.[9] Upon treatment with trifluorome-
thanesulfonic acid and phosphorus pentoxide, the corre-
[a] Dr. N. Holub, H. Jiang, Dr. M. W. Paix¼o, C. Tiberi,
Prof. Dr. K. A. Jørgensen
Center for Catalysis, Department of Chemistry
Aarhus University, 8000 Aarhus C (Denmark)
Fax : (+45)8619-6199
sponding racemic bicyclo
ACHTUNGTRNE[NUNG 2.2.2]oct-5-en-2-ones were ob-
E-mail: kaj@chem.au.dk
tained in good yields, although the highest yields were ob-
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ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4337

tained under additional microwave irradiation of the reac-
tion mixture.
Nowadays, organocatalysis has emerged as a powerful
tool for the introduction of chirality into a substrate,[10] and
the investigations of asymmetric organocatalytic processes
during the last few years included also Diels–Alder reac-
tions. In this context isoquinuclidines or amino-, hydroxyl-
and nitro-substituted bicycloACTHNUTRGENUGN[2.2.2]octanones have been syn-
thesised by cycloaddition of activated cyclohexenone deriva-
tives with imines, enolisable aldehydes or nitroolefins, re-
spectively.[11] Tan and Soh have utilised 3-hydroxy-2-pyri-
dones as dienes in an organocatalytic fashion, giving access
to azabicycloACHTUNGTRENNUNG a
[2.2.2]octenone frameworks,[11l] whereas
tandem strategy to build up bicycloACHTUNTRGNEUNG[3.3.1]nonanes has been
recently published by Tang and co-workers.[11m]
Despite the achievements published for the synthesis of
bicycloACHTUNGTRENNUNG[2.2.2]oct-5-en-2-one motifs, there is still need for a
general asymmetric approach. Herein, we present the asym-
metric organocatalytic synthesis of 6-alkyl- and 6-aryl-substi-
Scheme 2. Unexpected cyclisation reaction of alkyl-substituted Michael
adduct 5a. method A: Na2CO3, THF, iPrOH, 458C; method B: 1) 2-
ethyl-2-methyl-1,3-dioxolane, toluene sulfonic acid (pTSA), 2) saturated
aqueous solution of Na2CO3, tetrabutylammonium iodide (TBAI), tolu-
ene, 458C, 3) 50% aq. trifluoroacetic acid (TFA).
tuted bicycloACHTUNGTRENNUNG[2.2.2]oct-5-en-2-ones 4 in good yields and with
high enantioselectivities. The key step of this procedure is
based on the organocatalysed Michael reaction of cyclic
enones 1 with a b-keto benzothiazoyl (BT) sulfone 2, cata-
lysed by 9-amino-9-deoxyepiquinine trifluoroacetic acid salt
3[12] (Scheme 1). The resulting addition product can be utilis-
ed to build up the bicyclic core under mild conditions, by an
aldol reaction–Smiles rearrangement sequence. Depending
on the applied conditions, two possible mechanistic path-
ways can be considered, which also will be discussed herein.
product was identified as the bicyclic structure 4a, which, to
our delight, was formed with 90% enantiomeric excess (ee).
Due to the high enantiomeric excess generated in these
reactions, and the importance of bicycloACTHNUTRGNEUNG[2.2.2]oct-5-en-2-
ones in synthetic chemistry, we were interested in elucidat-
ing a plausible mechanism to explain the reaction course of
adduct 5a towards the bicyclic product 4a (Scheme 2). A
possible mechanism is outlined in Scheme 3, right. Starting
from the 1,4-addition intermediate 5, which was obtained in
a stereoselective manner in the organocatalytic cycle,[14] it is
assumed that the presence of Na2CO3 and a protic solvent,
such as iPrOH, results in the generation of small amounts of
the isopropoxide anion (method A). It is proposed that the
alkoxide performs a nucleophilic attack at the C=N carbon
atom of the heterocyclic ring in 6. Subsequent cleavage of
benzotriazolyl-OiPr (BT-OiPr) gives 7, and release of SO2
leads to the formation of the enolate anion 8. This removal
of the sulfone moiety can be considered as an intermolecu-
lar Smiles rearrangement.[15] Due to the presence of two
ketone functionalities, the equilibrium of the enolate species
8 and 9 seems to be dependent on the nature of the R sub-
stituent in the b-keto benzothiazoylsulfone. An aryl group
stabilises intermediate 8, thus making it possible to stop the
reaction at the 1,5-dicarbonyl compound,[13a] whereas an ali-
phatic R substituent will favour intermediate 9. An intramo-
lecular aldol reaction provides bicyclic structure 10 and sub-
sequent condensation finally results in the 6-alkyl-substitut-
Scheme 1. Organocatalytic synthesis of 6-alkyl- and 6-aryl-substituted
bicycloACHTUNGTRENNUNG[2.2.2]oct-5-en-2-ones.
Results and Discussion
In earlier work,[13] we have demonstrated that aryl-substitut-
ed Michael adducts A can be readily converted into desulfo-
nylated products B, or alkynylated products C, selectively,
depending on the applied reaction conditions (Scheme 2,
top).[13a] During these studies, we obtained unexpected re-
sults for the transformation of the alkyl-substituted adduct
5a (Scheme 2, bottom).
Upon treatment of 5a with solid Na2CO3 in a THF/iPrOH
mixture (method A, a procedure applied for removal of the
sulfone unit), or protection of the ketone group, followed by
treatment with an aqueous solution of Na2CO3 in the pres-
ence of tetrabutylammonium iodide (TBAI) as a phase-
transfer catalyst, (method B, conditions used for synthesising
b-alkynylated ketones), the same product 4a was obtained
in 43 and 62% yield, respectively. By 2D NMR analysis, the
ed bicycloACTHNUTRGNE[UNG 2.2.2]oct-5-en-2-one 4. To facilitate the cyclisation
for intermediate 9 with R=aryl, harsher conditions are be-
lieved to be required in analogy with the report of Jung and
Maderna,[9] using strongly acidic conditions in combination
with microwave irradiation.
To expand the scope of the reaction to alkyl and aryl sub-
stituents, a thorough screening of bases, solvents and addi-
tives was performed using cyclohexenone 1a and the alkyl-
substituted sulfone 2a as model substrates. The results are
presented in Table 1. Although this process is a clean reac-
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Asymmetric Organocatalysis
FULL PAPER
Scheme 3. Mechanistic aspects of the cyclisation reaction.
tion, under the initial reaction conditions, prolonged reac-
tion times were required. After 24 h at 458C, only 17% con-
version was achieved, and full conversion was only obtained
after three days (Table 1, entries 1 and 2). The use of
MeOH instead of iPrOH led to an increase in conversion
after 24 h (Table 1, entry 3). The reaction rate could be im-
proved by the use of stronger bases such as Cs2CO3 or
NaOMe (Table 1, entries 4 and 5). Full conversion was ob-
tained after 24 and 2 h, respectively, although the occur-
rence of side reactions resulted in low yields of 4a.
The base dependence on the reaction outcome led us to
investigate different reaction conditions (method B,
Scheme 2), in which a saturated aqueous solution of Na2CO3
in combination with a phase-transfer catalyst was employed.
Previously, these conditions were shown to favour the eno-
late Smiles rearrangement, leading to the formation of an
alkyne group in the ketal-protected Michael adducts (see
Scheme 2, middle).[13a] However, this alkyne formation was
only possible when using adduct 5, carrying R=aryl in the
sulfone moiety. For the aliphatic substrates, the bicyclic com-
pound 4 was formed exclusively, independent of the pres-
ence of the ketal protecting group. This was demonstrated
by subjecting the adduct 5a directly to the basic/phase-trans-
fer conditions (no ketal protection). After 24 h, we obtained
full conversion and 4a was formed in 58% yield with
95% ee (Table 1, entry 6). Access to ent-4a could be ach-
ieved by changing the catalyst employed (Table 1, entry 7).
As the organocatalytic Michael addition of aliphatic-substi-
tuted BT-sulfones normally results in prolonged reaction
times (48 h), we tried to perform this step at 458C (Table 1,
entry 8). Although full conversion was achieved after 28 h,
the enantiomeric excess of the product decreased to
92% ee. The two-step sequence can also be performed in a
one-pot procedure without affecting the enantioselectivity;
however, the isolated yield was slightly lower (42%,
94% ee).
With the optimised reaction conditions in hand, we
turned our attention to the application of this method to dif-
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4339

K. A. Jørgensen et al.
Table 1. Optimisation of the organocatalytic 1,4-addition of cyclohexe-
Table 2. Scope of the organocatalytic 1,4-addition of enones 1 with BT-
sulfones 2, followed by cyclisation to the bicycles 4.[a]
none 1a with BT-sulfone 2a, followed by cyclisation to bicycle 4a.[a]
Entry
1
Product
Yield [%][b]
ee [%][c]
4b 51
91
Entry
T
[8C]
Cyclisation conditions
Conv. Yield ee
2
3
4
4c 49
4d 44
4e 50
95
94
94
[%][b] [%][c] [%][d]
1
2
3
4
5
6
RT Na2CO3, THF/iPrOH, 458C, 24 h
RT Na2CO3, THF/iPrOH, 458C, 3 d
RT Na2CO3, THF/MeOH, 458C, 24 h
RT Cs2CO3, THF/iPrOH, 458C, 24 h
RT NaOMe, THF/iPrOH, 458C, 2 h
RT sat. Na2CO3, TBAI, toluene, 458C,
24 h
RT sat. Na2CO3, TBAI, toluene, 458C,
24 h
45
17
100
31
100
100
100
–
43
–
25
16
58
nd
90
nd
nd
nd
95
7[e]
8
100
100
60
54
À94
5
4 f 59
97
sat. Na2CO3, TBAI, toluene, 458C,
92
24 h
[a] Experimental conditions: enone 1a (1.0 mmol, 2 equiv) was added to
a stirred solution of 2a (0.5 mmol, 1 equiv) and catalyst 3 (20 mol%) in
dioxane (5 mL) at the indicated temperature. Then a solution of 5
6
4g 44
4h 51
60
98
(0.5 mmol) in
a 1:1 mixture toluene/saturated aqueous solution of
7[d]
Na2CO3 (10 mL) was treated with TBAI (1.2 equiv) and stirred at 458C.
[b] Determined by NMR spectroscopy. [c] Isolated yields. [d] Determined
by chiral stationary phase HPLC. [e] The quasi-enantiomer of 3 was
used.
[a] Experimental conditions: enone 1 (1.0 mmol, 2 equiv) was added to a
stirred solution of 2 (0.5 mmol, 1 equiv) and catalyst 3 (20 mol%) in di-
oxane (5 mL). Then, a solution of 5 (0.5 mmol) in a 1:1 toluene/saturated
aqueous solution of Na2CO3 (10 mL) was treated with TBAI (1.2 equiv)
and stirred at 458C. [b] Isolated yield. [c] Determined by chiral stationary
phase HPLC. [d] Reaction was performed at 658C.
ferent aromatic BT nucleophiles 2 (Table 2). As previously
stated, aryl-substituted nucleophiles did not undergo cyclisa-
tion when using sodium carbonate (method A, Scheme 2).
Having developed a more reactive process for obtaining the
bicyclic structures 4, we decided to apply these conditions to
the aryl-substituted sulfones. The phenyl-substituted sulfone
2b was selected and employed under these new conditions.
To our delight, full conversion of the cyclisation process was
obtained after 24 h. The 6-phenyl-substituted bicyclo-
Extension of this concept for the synthesis of bicyclo-
AHCTUNGTREG[NNNU 2.2.1]heptenone 4g was also achieved (Table 2, entry 6).
However, the modest enantioselectivity of 60% ee was con-
sistent with previously reported results for reactions of cy-
clopentenones.[16] Unfortunately, the synthesis of bicyclo-
AHCTUNGTREG[NNNU 3.2.2]nonenones failed and only the alkynylated ketone 4h
was isolated, although in good yield and with a very high ee
value (98% ee) (Table 2, entry 7). It should be pointed out
that in Table 2, entries 1–6, no alkyne products were ob-
served.
ACHTUNGTRENNUNG[2.2.2]oct-5-en-2-one 4b was isolated in 51% yield and with
a high enantioselectivity of 91% ee (Table 2, entry 1). Appa-
rently, by omitting ketal protection, alkyne formation was
completely suppressed, thus favouring the formation of the
6-aryl-substituted bicyclic compounds 4 (compare conditions
in Scheme 2, middle, with Table 2).
With these results in hand, the scope of this reaction is
not exclusively limited to the synthesis of 6-alkyl-substituted
bicycloACHTUNGTRENNUNG[2.2.2]oct-5-en-2-ones. A range of aromatic BT-sul-
fones was applied and the corresponding bicycles were iso-
lated in moderate yields (Table 2, entries 2–4); however, no
byproducts were detected. The nature and position of the
substituent attached to the aromatic ring have no influence
on the high enantioselectivities obtained (94–95% ee). An
increase of the steric bulk appears to be favourable, since
the 2-naphthyl substituent gave the highest yield and enan-
tioselectivity (59%, 97% ee, Table 2, entry 5).
Moreover, the application of this protocol to 5,5-dimeth-
yl-cyclohex-2-en-1-one 1d was also carried out (Scheme 4).
However, the bicyclic structures obtained were not consis-
tent with the expected results. By MS and NMR spectrosco-
py analysis, the products were identified as the diastereoiso-
mers trans-16 and trans-17, respectively. The formation of
these products can be rationalised by an additional attack of
BT-OH on the double bond. Surprisingly, depending on the
applied BT-sulfone, the corresponding trans-configured dia-
stereoisomers were formed with different selectivities.
Whereas R=Ph results in the formation of trans-16 with
high diastereoselectivity (95:5 diastereomeric ratio (d.r.)),
when R=alkyl, a 1:1 mixture of the two diastereomers
trans-17 was obtained.
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Asymmetric Organocatalysis
FULL PAPER
4 (suggesting a pathway from the favourable enolate 12
through alkyne product 15 to final product 4), isolated 15a
was subjected to the basic reaction conditions. This reaction
did not result in any formation of bicycle 4b (Scheme 5,
right), which supports the proposed alternative mechanism
(through the enolate 11) for the formation of the bicycles 4
when R=aryl.
It has previously been stated that under the present reac-
tion conditions, the ketal-protected adducts (R=aryl) give
the alkyne product 15 (Scheme 2, middle) This is rational-
ised by the fact that when the ketone functionality is pro-
tected, the acidity of the a-methylene protons is lowered to
the extent that the enolate 11 is not present. Therefore, the
transformation to the alkynylated product 15 becomes the
faster process, although small traces of the bicyclic com-
pound could be observed in the crude product mixture.
On the contrary, when R=alkyl, reasonable doubts can
be raised as to whether the aldol cyclisation takes place
prior to or after the desulfonylation step (Scheme 3, path-
way on the right vs. pathway on the left). An indication fa-
vouring the presence of a diketone intermediate (9) is that
even when the ketone motif is protected as a ketal and
when employing milder reaction conditions, the bicycle is
always formed as the sole product. As stated, masking the
ketone moiety raises the pKa of the a-methylene protons
significantly. Formation of a reactive anion in the presence
of the doubly activated methylene adjacent to the sulfone
seems unlikely. In the pathway on the right (Scheme 3), al-
though one activation group (sulfonyl) is removed, the acidi-
ty of the a-carbon atom of the ketal group is apparently
high enough to undergo intramolecular aldol reaction.
To summarise, it appears that the lack of the ketal moiety
favours, for R=aryl, the intramolecular aldol reaction of 13
(Scheme 3, pathway on the left). The formation of the b-al-
kynylated ketone 15 through the enolate Smiles rearrange-
ment can be completely suppressed. On the other hand,
product 15 was obtained in previous work selectively for
aryl substituents, by performing a protecting reaction before
applying the basic conditions. Therefore, the reaction out-
come for R=aryl is tuneable, whereas for aliphatic substitu-
ents, the formation of the bicyclic structure 4 is always pre-
ferred.
Scheme 4. Unexpected side reaction when 5,5-dimethyl cyclohexenone
1d was employed.
To obtain further insight into the mechanism for the for-
mation of the cyclic compounds with aromatic substituents,
a series of experiments was carried out. Attempts to trans-
form the pre-isolated aryl-substituted 1,5-diketone product
8a into its bicyclic counterpart 4b under the optimised reac-
tion conditions was unsuccessful (Scheme 5, left). This ob-
servation led us to believe that the presence of an intact BT-
sulfone group is crucial for the cyclisation of aryl-substituted
Michael adducts 5, hence it is less likely that the reaction
proceeds through a 1,5-diketone intermediate.
Scheme 5. Unsuccessful cyclisation reactions with isolated diketone 8a
and alkynylated ketone 15a.
The results prompted us to propose an alternative mecha-
nism for R=aryl, as presented in Scheme 3, left pathway.
When adduct 5 is subjected to Na2CO3 under phase-transfer
conditions, an equilibrium between enolates 11 and 12 fa-
vours 12. However, subsequent intramolecular aldol reac-
tion of 11 through nucleophilic attack of the cyclic enolate
anion takes place, giving the bicycle 13. Intermediate 13 un-
dergoes a Smiles rearrangement to give 14, followed by the
formation of bicyclo
G
Applications and transformations: The importance of
cause all reaction steps prior to the Smiles rearrangement
are reversible, the outcome of the reaction course is be-
lieved to be greatly influenced by the reaction rate of the
final step. Despite only small amounts of the unfavourable,
but reactive enolate 11 being present, the last irreversible
reactions from intermediate 13 to 4 are fast. It has been ob-
served that the transformation of 13 to 4 is completed
within hours, whereas the formation of the triple bond (12
to 15) requires days. The preference for the bicyclic com-
pound 4 is driven by a faster intramolecular Smiles rear-
rangement of 13 to 14, compared with the enolate Smiles re-
arrangement of 12 to 15. Furthermore, to rule out the possi-
bility of conversion from alkynylated products 15 to bicycles
bicycloACTHNGUTERN[UNG 2.2.2]oct-5-en-2-ones 4 in synthetic organic chemistry
is outlined in Figure 1. To further prove the value of these
optically active compounds, different transformations were
conducted for the 6-alkyl and 6-aryl substituted bicycles 4a
and 4d, respectively (Scheme 6). The reduction of the
double bond by palladium-catalysed hydrogenation resulted,
in both cases (R=alkyl 18, aryl 19) as a 1:3 mixture of dia-
stereoisomers, which could be separated by column chroma-
tography. NOE measurements confirmed the major diaste-
reoisomers to be 18 and 19, rationalised through attack op-
posite the methylene bridge, which provides more steric
bulk than the flat carbonyl moiety. In addition, pre-coordi-
nation of palladium to the carbonyl functionality could also
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4341

K. A. Jørgensen et al.
or ring-opening metathesis–cross metathesis (ROM–CM).
Compounds 23 and 24, chosen as adequate substrates for
RRM, were thus synthesised by the addition of allylmagne-
sium chloride to 4a or 4d, respectively. Unfortunately, also
in this case only a 1:1 mixture of diastereoisomers could be
obtained. On the other hand, application of the chiral
bicycloACTHNUTRGENUG[N 2.2.2]octenones 4 in ROMP would give access to
enantiopure polymers. Due to the different substitution pat-
tern on the olefinic side, selective ROM–CM processes can
be also considered, depending on the catalytic species utilis-
ed. An overview of these possible applications is given in
Scheme 7.
Finally, a stereoselective approach to chiral 5-hydroxy-
Scheme 6. Reduction and ring-expansion reactions of 4a and 4d.
bicycloACHTUNGTNER[NUNG 2.2.2]octanes has been achieved, further demonstrat-
ing the versatility of transformations performable with the
account for the stereochemical
outcome. Similarly, the reduc-
tion of the ketone functionality
with NaBH4 gave a 1:2 mixture
of inseparable isomers 22 in
quantitative yield. The major
isomer was assumed to result
from attack opposite the meth-
ylene bridge, in analogy with
the hydrogenation reaction pre-
viously discussed.
Two different ring-expanding
reactions were performed, start- Scheme 7. Possible applications of chiral bicyclo
ing from enantio- and diaste-
ACHTUNGTREN[NUNG 2.2.2]octenones 4.
reomerically pure 18, to confirm that regioselective access
to either bicyclic lactones or lactams (Scheme 6) is possible.
Treatment of 18 with meta-chloroperbenzoic acid (mCPBA)
resulted in the ring-expanding Baeyer–Villiger oxidation.
Surprisingly, the insertion of the oxygen atom occurred in
both possible positions, resulting in a 1:1 mixture of 2-
presented method. This compound class has been recently
transformed into a new ligand class (BODOL), which
proved to be efficient in asymmetric titanium-catalysed cate-
cholborane reductions.[20] As outlined earlier, the cyclisation
with aliphatic R substituents can be performed directly in
the presence of a ketal group. Compound 26 was therefore
synthesised directly, by applying the developed two-step se-
quence in an overall yield of 57% (Scheme 8). The protect-
ed ketone moiety enables subsequent hydroboration of the
double bond, giving rise to 27 as a single diastereoisomer.
The stereochemical outcome of this syn addition can be ra-
tionalised by coordination of borane to the ketal oxygen, re-
sulting in an attack from the lower side, in analogy to the
hydrogenation process (Scheme 6).
oxabicyclo
[3.2.2]nonan-2-one 20b. This effect has been reported earlier
in literature.[17] On the other hand, the Schmidt reaction[18]
of 4d gave exclusively the 3-aza-bicyclo[3.2.2]nonan-2-one
21.
As outlined before, bicyclo
ACHTUNGTRENNUNG[3.2.2]nonan-3-one 20a and 3-oxa-bicyclo-
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
AHCTUNGTERG[NNUN 2.2.2]octenones have been
often utilised for the anionic oxy-Cope rearrangement.[5]
Therefore, our aim was to transform 4a into the required
precursor for this rearrangement process (Scheme 7). Nucle-
ophilic attack of vinylmagnesium chloride at the ketone car-
bonyl group gave the corresponding tertiary alcohol 25 in
80% yield. However, an inseparable 1:1 mixture of diaste-
reoisomers was obtained. Since only one of the isomers un-
derwent the subsequent [3,3]-sigmatropic rearrangement, it
should be possible to resolve the mixture into the unreacted
isomer and the chiral decalin structure.[5a]
Conclusion
We have presented an easy, mild and organocatalytic ap-
proach to form highly enantioenriched 6-alkyl- and 6-aryl-
substituted bicycloACTHNUTRGENUG[N 2.2.2]oct-5-en-2-ones, by applying a two-
step sequence. The reaction can be also performed in a one-
pot procedure without loss of enantioselectivity. The bicy-
cles obtained, which are present in an array of natural prod-
ucts, were transformed into different building blocks, to be
used in, for example, ligand synthesis or rearrangement re-
actions.
Various bicycles of different sizes have been shown to be
suitable substrates for metathesis reactions.[19] The release of
ring strain as a driving force for these processes was exploit-
ed in ring-rearrangement metathesis (RRM) reactions, as
well as in ring-opening metathesis polymerisation (ROMP)
4342
www.chemeurj.org
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 4337 – 4346

Asymmetric Organocatalysis
FULL PAPER
HRMS: m/z: calcd for C16H18O+Na+: 249.1255 [M+Na+]; found:
249.1252. The ee value was determined by HPLC using a Chiralpak AS
column [hexane/iPrOH (98:2)]; flow rate 1.0 mLminÀ1; tmajor =13.4 min,
tminor =11.7 min (95% ee).
ACHUTNGRENUN(G 1S,4S)-6-PhenylbicycloACHTUNGTRENN[UGN 2.2.2]oct-5-en-2-one (4b): Prepared by following
the general procedure. Purification by FC (gradient: pentane to pentane/
EtOAc 2:1) gave 4b as a colourless oil (51% yield). [a]D =À131.0 (c=
1
0.22 in MeOH); H NMR (400 MHz, CDCl3): d=7.43–7.27 (m, 5H), 6.72
(d, J=6.7 Hz, 1H), 3.72–3.69 (m, 1H), 3.17–3.12 (m, 1H), 2.15–2.12 (m,
2H), 2.04–1.98 (m, 1H), 1.84–1.61 ppm (m, 3H); 13C NMR (100 MHz,
CDCl3): d=212.7, 140.1, 137.4, 130.7, 128.6(2C), 127.5, 125.1(2C), 51.1,
40.6, 32.6, 24.6, 22.8 ppm; HRMS: m/z: calcd for C14H14O+Na+:
221.0942 [M+Na+]; found: 221.0945. The ee value was determined by
HPLC using a Chiralpak AS column (hexane/iPrOH (98:2)); flow rate
1.0 mLminÀ1; tmajor =16.2 min, tminor =14.0 min (91% ee).
ACHUTNGRENUN(G 1S,4S)-6-(3-Chlorophenyl)bicycloAHCTUNGTREN[NGUN 2.2.2]oct-5-en-2-one (4c): Prepared by
Scheme 8. Synthesis of chiral 5-hydroxybicycloACTHNUGRTENUNG[2.2.2]octane 27.
following the general procedure. Purification by FC (gradient: pentane to
pentane/EtOAc 2:1) gave 4c (49% yield) as a colourless oil. [a]D =À66.0
(c=0.32 in MeOH); 1H NMR (400 MHz, CDCl3): d=7.39–7.37 (m, 1H),
7.28–7.23 (m, 3H), 6.75 (d, J=6.8 Hz, 1H), 3.67–3.63 (m, 1H), 3.18–3.14
(m, 1H), 2.14–2.12 (m, 2H), 2.07–1.98 (m, 1H), 1.83–1.61 ppm (m, 3H);
13C NMR (100 MHz, CDCl3): d=212.1, 139.2, 139.0, 134.6, 132.0, 129.8,
127.5, 125.3, 123.2, 51.0, 40.4, 32.6, 24.5, 22.7 ppm; HRMS: m/z: calcd for
C14H13ClO+Na+: 255.0553 [M+Na+]; found: 255.0544. The ee value was
determined by HPLC using a Chiralpak AS column (hexane/iPrOH
Experimental Section
General: 1H and 13C NMR spectra were acquired on a Varian AS 400
spectrometer, running at 400 and 100 MHz, respectively. Chemical shifts
(d) are reported in ppm relative to residual solvent signals (CHCl3, d=
7.26 ppm for H NMR; CDCl3, d=77.0 ppm for 13C NMR). The following
1
abbreviations are used to indicate the multiplicity in 1H NMR spectra: s,
singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad signal.
13C NMR spectra were acquired on a broad-band decoupled mode. For
characterisation of diastereomeric mixtures, *denotes minor diastereoiso-
mer, +denotes overlap of signals from both diastereoisomers. For approx-
imately 1:1 mixtures of diastereoisomers, no individual characterisation is
made. Mass spectra were recorded on a micromass LCT spectrometer by
using electrospray (ES+) ionisation techniques. Analytical TLC was per-
formed by using pre-coated aluminium-backed plates (Merck Kieselgel
60 F254) and visualised by ultraviolet irradiation or KMnO4 dip. Melting
points are uncorrected. Optical rotations were measured on a Perkin–
Elmer 241 polarimeter. The ee value of the products was determined by
chiral stationary phase HPLC (Daicel Chiralpak AS/AD and Daicel
Chiralcel OD/OJ columns).
(98:2)); flow rate 1.0 mLminÀ1
(95% ee).
;
tmajor =14.8 min, tminor =13.7 min
ACHUTNGRENUN(G 1S,4S)-6-(4-Fluorophenyl)bicycloAHCTUNGTREN[NGUN 2.2.2]oct-5-en-2-one (4d): Prepared by
following the general procedure. Purification by FC (gradient: pentane to
pentane/EtOAc 2:1) gave 4d as a colourless oil (44% yield). [a]D =
À162.0 (c=0.25 in MeOH); 1H NMR (400 MHz, CDCl3): d=7.39–7.32
(m, 2H), 7.02 (app. t, J=6.8 Hz, 2H), 6.66 (d, J=6.7 Hz, 1H), 3.66–3.63
(m, 1H), 3.17–3.11 (m, 1H), 2.14–2.12 (m, 2H), 2.05–1.97 (m, 1H), 1.84–
1.60 ppm (m, 3H); 13C NMR (100 MHz, CDCl3): d=212.5, 162.3 (d, J=
245.6 Hz), 139.1, 133.6 (d, J=3.2 Hz), 130.4, 126.7 (d, J=8.0 Hz, 2C),
115.5 (d, J=21.4 Hz, 2C), 51.3, 40.5, 32.5, 24.6, 22.7 ppm; HRMS: m/z:
calcd for C14H13FO+Na+: 239.0848 [M+Na+]; found: 239.0843. The ee
value was determined by HPLC using a Chiralpak AS column (hexane/
iPrOH (98:2)); flow rate 1.0 mLminÀ1; tmajor =17.5 min, tminor =12.8 min
(94% ee).
Materials: Unless otherwise noted, analytical grade solvents and commer-
cially available reagents were used without further purification. For flash
chromatography (FC), Iatrobeads (6R6S-8060) were used. Nucleophiles
2a–f,[13a] enone 1d[13a] and catalysts 3[12] were synthesised according to lit-
erature procedures. Racemic samples were prepared by using a racemic
mixture of the catalyst.
ACHUTNGRENUN(G 1S,4S)-6-p-TolylbicycloACHTUNGTRENN[UGN 2.2.2]oct-5-en-2-one (4e): Prepared by following
the general procedure. Purification by FC (gradient: pentane to pentane/
EtOAc 2:1) gave 4e as a colourless oil (50% yield). [a]D =À39.6 (c=
1
1.21 in CHCl3); H NMR (400 MHz, CDCl3): d=7.30 (d, J=8.0 Hz, 2H),
7.14 (d, J=7.9 Hz, 2H), 6.67 (d, J=6.8 Hz, 1H), 3.70–3.67 (m, 1H), 3.15–
3.10 (m, 1H), 2.34 (s, 3H), 2.14–2.11 (m, 2H), 2.05–1.96 (m, 1H), 1.83–
1.63 ppm (m, 3H); 13C NMR (100 MHz, CDCl3): d=212.8, 139.9, 137.4,
134.6, 129.7, 129.3(2C), 124.9(2C), 51.1, 40.7, 32.5, 24.6, 22.8, 21.1 ppm;
HRMS: m/z: calcd for C15H16O+Na+: 235.1098 [M+Na+]; found:
235.1099. The ee value was determined by HPLC using a Chiralpak AS
column (hexane/iPrOH (97:3)); flow rate 1.0 mLminÀ1; tmajor =7.8 min,
tminor =8.2 min (94% ee).
General procedure for the synthesis of bicycles 4: An ordinary vial
equipped with a magnetic stirring bar was charged with the nucleophile 2
(0.5 mmol, 1 equiv), the catalyst 3 (0.1 mmol, 0.2 equiv) and dioxane
(5 mL). Upon complete dissolution of the catalyst, enone 1 (1.0 mmol,
2.0 equiv) was added. The reaction mixture was stirred until complete
conversion of the nucleophile, as monitored by TLC or NMR spectrosco-
py (usually 24–48 h). Solvents were then removed in vacuo and the Mi-
chael adduct was purified on a short pad of Iatrobeads. The intermediate
obtained was re-dissolved in a 1:1 mixture of toluene, and a saturated
aqueous solution of Na2CO3 (10 mL) and TBAI (0.6 mmol, 1.2 equiv)
was added. The biphasic suspension was vigorously stirred for 24 h at
458C and then diluted with H2O (10 mL) and extracted with EtOAc (3ꢁ
10 mL). The combined organic phases were dried over MgSO4, concen-
trated in vacuo and purified by FC on Iatrobeads.
ACHUTNGRENUN(G 1S,4S)-6-(Naphthalen-2-yl)bicycloHCATUNGTREN[NGUN 2.2.2]oct-5-en-2-one (4 f): Prepared by
following the general procedure. Purification by FC (gradient: pentane to
pentane/EtOAc 2:1) gave 4 f as a colourless oil (59% yield). [a]D =À83.3
(c=0.68 in CHCl3); 1H NMR (400 MHz, CDCl3): d=7.85–7.76 (m, 4H),
7.60–7.54 (m, 1H), 7.50–7.42 (m, 2H), 6.87 (d, J=6.5 Hz, 1H), 3.88 (app.
s, 1H), 3.22–3.17 (m, 1H), 2.20–2.16 (m, 2H), 2.10–2.05 (m, 1H), 1.90–
1.65 ppm (m, 3H); 13C NMR (100 MHz, CDCl3): d=212.7, 139.9, 134.4,
132.8, 131.2, 129.6, 128.3, 128.1, 127.5, 126.4, 126.0, 123.6, 123.3, 51.0,
40.7, 32.7, 24.7, 22.8 ppm; HRMS: m/z: calcd for C18H16O+Na+:
271.1098 [M+Na+]; found: 271.1099. The ee value was determined by
HPLC using a Chiralpak AS column (hexane/iPrOH (98:2)); flow rate
1.0 mLminÀ1; tmajor =12.8 min, tminor =13.6 min (97% ee).
ACHTUNGTRENNUNG(1S,4S)-6-PhenethylbicycloACHTUNGTERN[NUGN 2.2.2]oct-5-en-2-one (4a): Prepared by follow-
ing the general procedure. Purification by FC (gradient: pentane to pen-
tane/EtOAc 2:1) gave 4a as a colourless oil (58% yield). [a]D =À103.1
(c=1.0 in CHCl3); 1H NMR (400 MHz, CDCl3): d=7.30–7.24 (m, 2H),
7.21–7.13 (m, 3H), 6.05 (d, J=6.6 Hz, 1H), 3.08–3.05 (m, 1H), 2.92–2.87
(m, 1H), 2.80–2.65 (m, 2H), 2.47–2.40 (m, 2H), 2.01–1.99 (m, 2H), 1.90–
1.82 (m, 1H), 1.72–1.63 (m, 1H), 1.61–1.52 (m, 1H), 1.52–1.43 ppm (m,
1H); 13C NMR (100 MHz, CDCl3): d=213.4, 141.4, 140.6, 129.3,
128.3(2C), 128.3(2C), 125.9, 52.8, 41.1, 36.1, 33.9, 32.0, 24.9, 22.4 ppm;
ACHUTNGRENUN(G 1S,4S)-6-PhenylbicycloACHTUNGTRENN[UGN 2.2.1]hept-5-en-2-one (4g): Prepared by follow-
ing the general procedure. Purification by FC (gradient: pentane to pen-
tane/EtOAc 2:1) gave 4g as a colourless oil (44% yield). [a]D =À46.3
(c=1.1 in CHCl3); 1H NMR (400 MHz, CDCl3): d=7.45–7.40 (m, 2H),
Chem. Eur. J. 2010, 16, 4337 – 4346
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
4343

K. A. Jørgensen et al.
7.35–7.29 (m, 3H), 6.72 (d, J=2.9 Hz, 1H), 3.49 (app. s, 1H), 3.31 (app. s,
1H), 2.43–2.38 (m, 1H), 2.13 (d, J=9.3 Hz, 1H), 2.08 (d, J=3.3 Hz, 1H),
2.00 (d, J=4.3 Hz, 1H); 13C NMR (100 MHz, CDCl3): d=215.2, 144.2,
135.3, 128.6(2C), 127.8, 127.2, 125.1(2C), 57.8, 50.1, 40.6, 37.8 ppm;
HRMS: m/z: calcd for C13H12O+Na+: 207.0786 [M+Na+]; found:
207.0797. The ee value was determined by HPLC using a Chiralpak AS
column (hexane/iPrOH (98:2)); flow rate 1.0 mLminÀ1; tmajor =8.6 min,
tminor =11.1 min (60% ee).
1.31–1.16 ppm (m, 1H); 13C NMR (100 MHz, CDCl3): d=217.0, 141.9,
141.8, 128.4 (2C), 128.4 (2C), 128.3(2C), 128.3(2C), 125.9, 125.8, 47.5,
46.8, 44.8, 43.6, 39.1, 36.1, 35.6, 33.6, 33.4, 33.0, 32.7, 31.9, 28.2, 28.1, 25.2,
23.8, 23.3, 17.5 ppm; HRMS: m/z: calcd for C16H20O+Na+: 251.1412
[M+Na+]; found: 251.1412.
A
E
and
AHCTUNGTRENNUNG
20b): mCPBA (0.8 mmol, 4 equiv) was added to a stirred solution of 18
(0.2 mmol) in CH2Cl2 (0.5 mL) at 08C. Upon completion of the reaction,
the reaction mixture was diluted with EtOAc (5 mL), washed with a satu-
rated aqueous solution of sodium thiosulfate (2 mL) and brine (2 mL).
The organic phase was dried over MgSO4, concentrated in vacuo and pu-
rified by FC on silica gel (gradient: pentane/EtOAc 4:1 to pentane/
EtOAc 2:1) to afford the regioisomers 20a and 20b as a colourless oil
(S)-3-((4-Fluorophenyl)ethynyl)cycloheptanone (4h): Prepared by follow-
ing the general procedure, but by performing the organocatalytic step at
458C and the cyclisation step at 658C. Purification by FC (gradient: pen-
tane to pentane/EtOAc 2:1) gave 4h as a colourless oil (51% yield).
1
[a]D =+6.6 (c=1.3 in CHCl3); H NMR (400 MHz, CDCl3): d=7.37–7.33
(m, 2H), 6.97 (t, J=8.8 Hz, 2H), 3.11–3.05 (m, 1H), 2.79 (d, J=5.8 Hz,
2H), 2.68–2.49 (m, 2H), 2.07–1.90 (m, 3H), 1.83–1.67 ppm (m, 3H);
13C NMR (100 MHz, CDCl3): d=212.3, 162.2 (d, J=247.3 Hz), 133.3 (d,
J=8.3 Hz, 2C), 119.3 (d, J=3.6 Hz), 115.4 (d, J=21.8 Hz, 2C), 90.6 (d,
J=1.5 Hz), 82.4, 48.8, 44.0, 36.3, 27.8, 27.3, 23.9 ppm; HRMS: m/z: calcd
for C15H15FO+Na+: 253.1004 [M+Na+]; found: 253.1005. The ee value
was determined by HPLC using a Chiralpak AS column (hexane/iPrOH
1
(60% combined yield, ratio 1:1). [a]D =À1.5 (c=0.5 in CHCl3); H NMR
(400 MHz, CDCl3): d=7.30–7.23 (m, 4H), 7.04–6.97 (m, 4H), 4.56–4.28
(m, 2H), 3.13–2.73 (m, 6H), 2.44–2.19 (m, 6H), 2.12–2.00 (m, 2H), 1.90–
1.71 ppm (m, 6H); 13C NMR (100 MHz, CDCl3): d=173.7 (2C), 161.8 (d,
J=243.5 Hz, 2C), 138.4 (d, J=3.8 Hz, 2C), 129.3 (d, J=7.8 Hz, 2C), 128.8
(d, J=7.9 Hz, 2C), 115.4 (d, J=21.1 Hz, 2C), 115.3 (d, J=21.0 Hz, 2C),
78.2, 75.2, 47.0, 42.7, 42.3, 39.8, 32.7, 31.3, 30.5, 28.1, 25.4, 24.2, 23.7,
22.7 ppm; HRMS: m/z: calcd for C14H15FO2 +Na+: 257.0954 [M+Na+];
found: 257.0951.
(98:2)); flow rate 1.0 mLminÀ1
(98% ee).
;
tmajor =23.5 min, tminor =20.5 min
(1R,4S,5S,6R)-5-(Benzo[d]thiazol-2-yloxy)-2,2-dimethyl-6-phenylbicyclo-
[2.2.2]octan-7-one (trans-16): Prepared by following the general proce-
G
ACHUTGTNRNE(NUG 1S,5R,7S)-7-(4-Fluorophenyl)-3-azabicycloCAHTUNGTRNEN[GUN 3.2.2]nonan-2-one (21): NaN3
dure. Purification by FC (gradient: pentane to pentane/EtOAc 2:1) gave
16 as a colourless oil (54% yield, d.r. 5:95). [a]D =À4.7 (c=1.0 in
CH2Cl2); 1H NMR (400 MHz, CDCl3): d=7.99 (d, J=8.2 Hz, 1H), 7.87
(app. d, J=7.2 Hz, 3H), 7.55–7.35 (m, 5H), 5.32 (s, 1H), 3.51–3.43 (m,
1H), 3.16 (dd, J=8.6, 17.9 Hz, 1H), 2.99 (dd, J=3.3, 18.0 Hz, 1H), 2.81
(d, J=12.4 Hz, 1H), 2.70 (dd, J=0.9, 12.4 Hz, 1H), 1.79–1.64 (m, 2H),
1.24 (s, 3H), 1.10 ppm (s, 3H); 13C NMR (100 MHz, CDCl3): d=208.0,
172.5, 152.5, 136.7, 135.9, 133.3, 128.5(2C), 128.1(2C), 126.0, 125.2, 123.1,
121.8, 82.1, 49.2, 40.6, 39.4, 38.7, 35.3, 31.4, 27.6(2C) ppm; HRMS: m/z:
calcd for C23H23KNO2S+: 416.1087 [M+H+]; found: 416.1250.
(0.09 mmol, 1.2 equiv, in 30 mL H2O) was carefully added to a stirred so-
lution of 18 (0.08 mmol, 1.0 equiv) in TFA (0.8 mL). The reaction mix-
ture was stirred at RT for 30 min and then heated at 508C for 4 h. Upon
completion of the reaction, H2O and solid NaHCO3 were carefully added
and the aqueous phase was extracted with EtOAc (3ꢁ5 mL). The com-
bined organic phases were dried over MgSO4, concentrated in vacuo and
purified by FC on silica gel (gradient: pentane/EtOAc 4:1 to pure
EtOAc) to give 21 as a colourless oil (90% yield). [a]D =À9.5 (c=0.5 in
CHCl3); 1H NMR (400 MHz, CDCl3): d=7.19 (dd, J=5.3, 8.7 Hz, 2H),
6.95 (s, 1H), 6.89 (t, J=8.7 Hz, 2H), 3.25 (app. s, 2H), 3.05 (app. s, 1H),
2.97 (dt, J=2.6, 9.7 Hz, 1H), 2.47–2.42 (m, 1H), 2.32–2.15 (m, 2H), 2.02–
1.70 ppm (m, 4H); 13C NMR (100 MHz, CDCl3): d=179.0, 161.6 (d, J=
243.0 Hz), 139.6 (d, J=3.0 Hz), 129.0 (d, J=7.8 Hz, 2C), 115.1 (d, J=
20.9 Hz, 2C), 49.3, 46.2, 41.0, 31.7, 29.2, 24.7, 24.3 ppm; HRMS: m/z:
calcd for C14H16NFO+Na+: 256.1114 [M+Na+]; found: 256.1117.
(1R,4S,5S,6S)-5-(Benzo[d]thiazol-2-yloxy)-2,2-dimethyl-6-phen-
ethylbicycloACHTUNGTRENNUNG[2.2.2]octan-7-one (trans-17): Prepared by following the gen-
eral procedure. Purification by FC (gradient: pentane to pentane/EtOAc
2:1) gave 17 as a colourless oil (59% yield, d.r. 1:1). [a]D =+10.7 (c=2.1
1
in CHCl3); H NMR (400 MHz, CDCl3): d=8.08–8.03 (m, 2H), 7.89–7.85
(m, 2H), 7.54–7.47 (m, 2H), 7.42–7.36 (m, 2H), 7.28–7.20 (m, 10H),
5.19–5.16 (m, 2H), 3.64 (s, 4H), 3.23–3.09 (m, 2H), 2.77–2.61 (m, 2H),
2.39–2.28 (m, 2H), 2.28–2.19 (m, 1H), 2.08–1.97 (m, 4H), 1.80 (t, J=
14.0 Hz, 1H), 1.63 (t, J=13.2 Hz, 1H), 1.43 (d, J=13.2 Hz, 1H), 1.29–
1.16 (m, 4H), 0.97 (s, 3H), 0.81 (s, 3H), 0.80 (s, 3H), 0.69 ppm (s, 3H);
13C NMR (100 MHz, CDCl3): d=206.6, 206.5, 172.9, 172.8, 153.3, 153.2,
135.7, 135.7, 134.3, 134.2, 130.2(2C), 130.2(2C), 128.2(2C), 128.2(2C),
127.3, 127.3, 126.2(2C), 125.3(2C), 123.0, 123.0, 121.9, 121.8, 84.4, 84.3,
60.3(2C), 54.1(2C), 46.4, 46.0, 44.7, 44.6, 44.4, 44.1, 43.1, 43.1, 34.9, 34.7,
31.8, 31.6, 30.4, 30.2, 25.4, 25.3 ppm.
ACHUTGTNRNE(NUG 1S,4S)-6-PhenethylbicycloCAHTUTGNREN[NGUN 2.2.2]oct-5-en-2-ol (22): NaBH4 (0.05 mmol,
1.5 equiv) was added to a stirred solution of 4a (0.03 mmol) in THF
(1 mL) at 08C, followed by MeOH (0.3 mL). The mixture was stirred for
1 h, then quenched by the addition of a saturated aqueous solution of
NH4Cl and extracted with CH2Cl2. After drying over MgSO4 the solvent
was removed in vacuo and the residue purified by FC (gradient: pentane
to pentane/EtOAc 3:1) to provide 22 as a colourless oil (99% yield, d.r.
1
1:2). H NMR (400 MHz, CDCl3): d=7.30–7.26+ (m, 4H), 7.23–7.16+ (m,
6H), 6.05 (dd, J=1.4, 6.6 Hz, 1H), 5.88* (dd, J=1.4, 6.4 Hz, 1H), 3.97–
3.92 (m, 1H), 3.85–3.80* (m, 1H), 2.83–2.37+ (m, 12H), 2.08–1.89+ (m,
2H), 1.43–1.05+ ppm (m, 12H); 13C NMR (100 MHz, CDCl3): d=142.1,
141.8*, 128.4, 128.3*, 128.3+(4C), 128.3+(2C) 127.5, 127.3*, 125.8+(4C),
70.7, 69.6*, 42.3*, 42.1, 39.2, 37.8, 36.7*, 36.5*, 34.1*, 33.9, 30.4*, 29.8,
26.7*, 24.8, 21.8, 17.4* ppm; HRMS: m/z: calcd for C16H20O+Na+:
251.1411 [M+Na+]; found: 251.1412.
ACHTUNGTRENNUNG(1S,4R)-6-(4-Fluorophenyl)bicycloCAHTUNGTREN[NGUN 2.2.2]octan-2-one (18): A suspension
of compound 4d (0.2 mmol) and 20% Pd(OH)2/C (15 mg) in MeOH
(1.5 mL) was stirred under a hydrogen atmosphere at 208C for 12 h. The
reaction mixture was filtered through a pad of silica and the filtrate was
concentrated under reduced pressure. Purification of the residue by FC
(gradient: pentane to pentane/EtOAc 4:1) afforded compound 18 as a
General procedure for the Grignard addition: A dry Schlenk tube was
charged with compound 4 (0.2 mmol) and THF (1.5 mL) and cooled to
À208C. The Grignard reagent (1m solution in THF, 0.25 mmol,
1.25 equiv) was added dropwise by syringe at À208C. The mixture was al-
lowed to warm to RT over a period of 2 h, and stirred overnight, before a
saturated aqueous solution of NH4Cl (1 mL) was added, followed by a
2n aqueous solution of HCl (1 mL). The organic layer was extracted
with EtOAc (2ꢁ3 mL). The combined organic layers were dried over
MgSO4, concentrated and purified by FC (gradient: pentane to pentane/
EtOAc 2:3) to afford the corresponding tertiary alcohols.
1
colourless oil (94% yield, d.r. 1:3). H NMR (400 MHz, CDCl3): d=7.11–
7.05 (m, 2H), 6.98–6.92 (m, 2H), 3.30–3.20 (m, 1H), 2.45–2.26 (m, 5H),
2.01–1.61 ppm (m, 5H); 13C NMR (100 MHz, CDCl3): d=216.2, 216.2*,
161.5* (d, J=243.5 Hz), 161.3 (d, J=243.1 Hz), 141.2 (d, J=3.0 Hz),
137.8* (d, J=3.3 Hz), 129.1* (d, J=7.8 Hz, 2C), 128.3 (d, J=7.9 Hz, 2C),
115.3+ (d, J=21.1 Hz, 4C), 49.2*, 48.7, 45.2, 43.5*, 41.8, 37.4*, 35.1, 30.9*,
28.3*, 27.7, 25.2*, 24.3, 23.2, 17.3* ppm; HRMS: m/z: calcd for
C14H15FO+Na+: 241.1006 [M+Na+]; found: 241.1005.
ACHTUNGTRENNUNG(1S,4R)-6-PhenethylbicycloACHTUNTGREN[NUGN 2.2.2]octan-2-one (19): Prepared by following
the same procedure as above for compound 18, compound 19 was isolat-
ed (81% yield, d.r. 1:3) as a colourless oil. 1H NMR (400 MHz, CDCl3):
d=7.29–7.24 (m, 2H), 7.20–7.13 (m, 3H), 2.62 (t, J=7.8 Hz, 2H), 2.27–
2.15 (m, 4H), 2.05–1.86 (m, 3H), 1.84–1.76 (m, 2H), 1.67–1.43 (m, 5H),
ACHUTGTNRENN(GU 1S,4S)-2-Allyl-6-(4-fluorophenyl)bicycloACHTUNGTERN[NUGN 2.2.2]oct-5-en-2-ol (23): Follow-
ing the general procedure, treatment of 4d with allylmagnesium chloride
gave 23 (79% yield, d.r. 1:1) as a colourless oil. 1H NMR (400 MHz,
CDCl3): d=7.45–7.36+ (m, 4H), 7.05–6.98+ (m, 4H), 6.57* (dd, J=1.6,
4344
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ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 4337 – 4346

Asymmetric Organocatalysis
FULL PAPER
6.7 Hz, 1H), 6.46 (dd, J=1.6, 6.7 Hz, 1H), 6.09–5.98* (m, 1H), 5.79 (ddt,
J=1.4, 10.2, 17.5 Hz, 1H), 5.23–4.96+ (m, 4H), 3.07–3.05* (m, 1H), 2.93–
2.90 (m, 1H), 2.79–2.72+ (m, 2H), 2.53* (ddt, J=1.2, 6.7, 14.0 Hz, 1H),
2.40* (dd, J=14.0, 7.7 Hz, 1H), 2.32–2.24 (m, 1H), 2.14–2.09+ (m, 2H),
2.18–2.06 (m, 1H), 1.81–1.65+ (m, 4H), 1.58–1.16+ ppm (m, 8H);
13C NMR (100 MHz, CDCl3): d=162.1* (d, J=244.1 Hz), 162.0 (d, J=
244.3 Hz), 143.2, 142.6*, 135.8* (d, J=3.3 Hz), 135.1 (d, J=2.9 Hz),
134.3*, 133.3, 128.7*, 128.1, 126.6* (d, J=7.7 Hz, 2C), 126.2 (d, J=
7.7 Hz, 2C), 119.7, 118.2*, 115.3 (d, J=21.2 Hz, 2C), 115.2* (d, J=
21.1 Hz, 2C), 75.1, 74.9*, 47.4, 44.8*, 44.7*, 43.8, 43.6*, 41.4, 31.8, 31.3*,
24.9, 23.9*, 21.0*, 20.0 ppm; HRMS: m/z: calcd for C17H19FO+Na+:
281.1318 [M+Na+]; found: 281.1318.
110.5, 76.4, 64.1, 63.3, 46.4, 39.1, 36.5, 36.2, 35.0, 34.5, 23.3, 17.2 ppm;
HRMS: m/z: calcd for C18H24O3 +Na+: 311.1623 [M+Na+]; found:
311.1624.
Acknowledgements
This work was made possible by a grant from The Danish National Re-
search Foundation, OChemSchool and theCarlsberg Foundation. Thanks
are expressed to Deutsche Forschungsgemeinschaft (N.H.) and MIUR
and University of Florence (C.T.). The authors thank all referees for
their much-appreciated work and their help in improving the quality of
this manuscript.
ACHTUNGTRENNUNG(1S,4S)-2-Allyl-6-phenethylbicycloHCATUNGTREN[NGUN 2.2.2]oct-5-en-2-ol (24): Following the
general procedure, treatment of 4a with allylmagnesium chloride gave 24
as a colourless oil (71% yield, d.r. 1:1). 1H NMR (400 MHz, CDCl3): d=
7.31–7.26 (m, 2H), 7.23–7.16 (m, 3H), 6.02–5.84 (m, 2H), 5.21–5.08 (m,
2H), 2.88–2.65 (m, 2H), 2.56–2.51 (m, 1H), 2.49–2.40 (m, 3H), 2.36–2.27
(m, 1H), 2.19–2.07 (m, 2H), 1.68–1.02 ppm (m, 6H); 13C NMR
(100 MHz, CDCl3): d=145.0, 144.4, 142.2, 134.6, 133.7, 128.3, 128.3,
126.5, 125.8, 125.7, 125.6, 119.4, 117.9, 75.0, 74.9, 47.5, 45.6, 45.1, 44.9,
44.7, 42.2, 37.7, 37.0, 33.8, 33.7, 31.1, 30.7, 25.2, 24.7, 21.0, 19.9 ppm;
HRMS: m/z: calcd for C19H24O+Na+: 291.1725 [M+Na+]; found:
291.1728.
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general procedure, treatment of 4a with vinylmagnesium chloride gave
25 as a colourless oil (80% yield, d.r. 1:1). 1H NMR (400 MHz, CDCl3):
d=7.30–7.26 (m, 2H), 7.23–7.17 (m, 3H), 6.09–5.79 (m, 2H), 5.38–4.90
(m, 2H), 2.80–2.33 (m, 6H), 1.73–1.10 ppm (m, 6H); 13C NMR
(100 MHz, CDCl3): d=146.9, 144.8, 142.6, 142.1, 129.7, 128.6, 128.6,
128.5, 128.5, 128.0, 127.0, 126.3, 126.1, 126.0, 112.9, 110.1, 76.1, 76.1, 47.3,
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ACHTUNGTRENNUNG(1S,4S)-6-phenethylspiroACHTUNGTRENNUNG[bicycloACHTNUGTNER[NUGN 2.2.2]oct[5]-ene-2,2’-[1,3]-dioxolane]
(26): An ordinary vial equipped with a magnetic stirring bar was charged
with the nucleophile 2a (0.5 mmol, 1 equiv), the catalyst 3 (0.1 mmol,
0.2 equiv) and dioxane (5 mL). Upon complete dissolution of the catalyst,
enone 1a (1.0 mmol, 2.0 equiv) was added. The reaction mixture was
stirred for 48 h. Solvents were removed in vacuo and the Michael adduct
5a was purified on a short pad of Iatrobeads. The obtained intermediate
was dissolved in toluene (1 mL), treated with 2-ethyl-2-methyl-1,3-dioxo-
lane (15 mmol, 30 equiv) and pTSA (0.15 mmol, 0.3 equiv). After stirring
for 24 h, the mixture was diluted with EtOAc, washed with a saturated
aqueous solution of NaHCO3 and concentrated in vacuo. The obtained
residue was re-dissolved in a 1:1 mixture of toluene and a saturated aque-
ous solution of Na2CO3 (10 mL), and TBAI (0.6 mmol, 1.2 equiv) was
added. The biphasic suspension was vigorously stirred for 24 h at 458C
and then diluted with H2O (10 mL) and extracted with EtOAc (3ꢁ
10 mL). The combined organic phases were dried over MgSO4, concen-
trated in vacuo and purified by FC on Iatrobeads (gradient: pentane to
pentane/EtOAc 4:1) to give 26 as a colourless oil (57% yield over 3
steps). [a]D =À16.7 (c=0.9 in CHCl3); 1H NMR (400 MHz, CDCl3): d=
7.31–7.16 (m, 5H), 5.93 (dd, J=1.4, 6.5 Hz, 1H), 3.94–3.90 (m, 4H),
2.80–2.75 (m, 2H), 2.62–2.57 (m, 1H), 2.50–2.32 (m, 3H), 1.94–1.83 (m,
2H), 1.74–1.30 ppm (m, 4H); 13C NMR (100 MHz, CDCl3): d=144.0,
142.4, 131.3, 128.3(2C), 128.2(2C), 125.9, 125.7, 64.0, 63.9, 42.5, 41.2, 37.1,
33.8, 30.8, 24.9, 20.5 ppm.
(1S,4S,5R,6R)-6-PhenethylspiroACTHNUTRGENNG[U bicycloACHTUNGTNER[NUGN 2.2.2]-octane-2,2’-[1,3]-dioxo-
lan]-5-ol (27): BH3-Me2S (0.08 mmol, 1.5 equiv) was added dropwise to a
stirred solution of 26 (0.06 mmol) in THF (0.3 mL) at 08C. The reaction
mixture was stirred for 3 h at 08C and then allowed to reach RT over-
night. A 3n aqueous solution of NaOH (20 mL) and a 30% aqueous solu-
tion of H2O2 (20 mL) were added and the solution was stirred for 4 h,
then diluted with diethyl ether and washed with brine. After drying over
MgSO4, the organic phase was concentrated in vacuo and purified by FC
(gradient: pentane to pentane/EtOAc 4:1) to give 27 as a pale yellow oil
(40% yield over 2 steps). [a]D =À12.0 (c=0.1 in CHCl3); 1H NMR
(400 MHz, CDCl3): d=7.30–7.17 (m, 5H), 3.96–3.79 (m, 4H), 3.66–3.61
(m, 1H), 2.75–2.65 (m, 2H), 2.03–1.68 (m, 8H), 1.52–1.30 ppm (m, 4H);
13C NMR (100 MHz, CDCl3): d=142.8, 128.4(2C), 128.3(2C), 125.6,
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Received: November 30, 2009
Published online: March 10, 2010
4346
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Chem. Eur. J. 2010, 16, 4337 – 4346